Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism

Nat Med. 2000 Feb;6(2):151-8. doi: 10.1038/72247.

Abstract

Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by unknown mechanisms, induce widespread inflammation. We found that a large proportion of primary spinal afferent neurons, which express proteinase-activated receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related peptide and substance P. Trypsin and tryptase directly signal to neurons to stimulate release of these neuropeptides, which mediate inflammatory edema induced by agonists of proteinase-activated receptor 2. This new mechanism of protease-induced neurogenic inflammation may contribute to the proinflammatory effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists of proteinase-activated receptor 2 may be useful anti-inflammatory agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Calcitonin Gene-Related Peptide / metabolism
  • Chymases
  • DNA Probes
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Humans
  • In Situ Hybridization
  • Inflammation / etiology*
  • Male
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor, PAR-2
  • Receptors, Thrombin / agonists*
  • Receptors, Thrombin / metabolism
  • Serine Endopeptidases / metabolism
  • Signal Transduction
  • Substance P / metabolism
  • Trypsin / metabolism
  • Tryptases

Substances

  • DNA Probes
  • Receptor, PAR-2
  • Receptors, Thrombin
  • Substance P
  • Serine Endopeptidases
  • chymase 2
  • Chymases
  • Trypsin
  • TPSB1 protein, rat
  • Tpsb2 protein, rat
  • Tryptases
  • Calcitonin Gene-Related Peptide